Biomed & Phannacorher ( 1993) 47. 363-370 0 Elsevier. Paris 363 Dossier “Cancer” The (Sthiotheophyllinate) (triphenylphosphine) Gold (I), (tTAUP): a new gold complex as an anticancer agent A Garcia-Orad’, P Arizti’, F Sommer4, L Silvestro5, P Massio@, P Chevallier, JM Gutierrez-Zorrilla’, E Colacio3, M Martinez de Pancorbo’, H Tapiero7 ‘Dpro de Biologia Celular. ‘Dpto de Quimica Inorganica, Univemidad Pais Vasco. Leioa. Vizcaya: ‘Dpfo de Quimica Inorganica. Universidad de Gionada, Spain; Luboratoire de Biophvsique: Faculre de MPdecine de Creteil. France; Istitito di Farmacologia, Facolta di Medkina; ‘Universita di Torino. Ita1.v: Laboraroire Pierre Sue. CEN Saclay. France: “LPAN. UniversirP Pierre et Mnrie Curie et Lure. Orsay. France; 7Dpt of Cell and Mol Phannacol. ICIG. H6pital Paul Browse. 94800 Villejuif, France (Received 16 August 1993; accepted 10 September 1993) Summary - In continuous Friend leukemia cell exposure to tTAuP, the IC50 was 0.2 pM whereas in cells exposed 15 or 60 min to tTAuP followed by 72 h in drug-free medium the IC50 was 2.2 and 1.3 pM respectively. A combination of tTAuP and cisplatin (CDDP) is shown to be more active than either agent alone. Intracellular accumulation studies analysed by SXRF have shown that to achieve a cytotoxic effect, large concentrations of gold are necessary to accumulate in both the nuclear and cytoplasmic fraction. However, at cytostatic doses (1 PM), tTAuP has no effect on the cell cycle but does affect DNA synthesis. At a higher dose, greater than that necessary to induce cytotoxicity, it produces DNA damage, as observed by alkaline elution method. When cells were exposed to toxic doses of tTAuP (10 FM) in the presence of albumin, cytotoxicity was significantly reduced. Similar results were obained when cells were co-treated with L-cysteine, dithiothreitol or reduced gluthatione. Reduced cytotoxic effect can be related to the interaction with free thiol groups. According to these data it is concluded that tTAuP is highly effective in vitro; whether it is active in vivo remains to be determined. gold complexes I platin salts I cytotoxicity DNA / Thiois Introduction The biological use of gold compounds in medi- cine has been known for centuries. It was recom- mended as treatment against leprosy by Bacon (1561-1626). The German bacteriologist Koch discovered that the dicyanogold(I) complex is toxic for tuberculosis bacilli [14]. There were re- ports of beneficial effects and many gold (I) com- Abbreviations: tTAup: @-Thiotheophyllinate)(triphenyl- phosphine)gold(I); PBS: Phosphate Buffer Saline; FCS: Fetal Calf Serum; FLC: Friend Leukemia Cells DOX- RFLC (Doxorubicine Resistant FLC; SXRF: Syn- chrotron Radiation X-Ray Fluorescence. pounds were subsequently synthesized which might have less severe side effects. In 1927 Lande [ 161 and Forestier [lo] first used gold compounds in patients with arthritis to relieve joint pain. The most remarkable drugs ac- cepted in rheumatoid arthritis therapy have been Myocrisin (disodiumthiomalatogold (I), Solganal (thioglucosegold(1)) SK36914 (Chlorotriethyl- phosphine gold(I) and Auranofin (2,3,4,6-O-acetyl- 1-tio-beta-D-Glucopyranosate) (triethylphosphine gold(I). Gold complexes have also shown cyto- toxic and antitumoral properties [2, 19, 20, 321. Gold compounds with a co-ordinated phosphine ligand and a thiol group bound to gold have shown to be the most active ones [21]. A number of gold (I) compounds, with sulfur and/or phos-